Expert Critique

As the number of FDA-approved indications for immune checkpoint inhibitors has increased in recent years and there hasn’t been a dramatic decrease in incidence or prevalence of the cancers eligible for treatment with immune checkpoint inhibitors, more patients are receiving immune checkpoint inhibitors to treat their cancers. For some tumor types at some stages of disease, no particular biomarker is needed to determine eligibility for immune checkpoint inhibitor therapy (though which the immune checkpoint inhibitor to be used depends on specific tissue type):
-- Stage 3 non-small cell lung cancer after definitive treatment and response with chemoradiation
-- Stage 4 non-small cell lung cancer after progressive following platinum-based chemotherapy (if EGFR or ALK mutated, targeted therapy to be tried before eligible for immune checkpoint inhibitors)
-- Extensive-stage small cell lung cancer in the second line
-- Stage 3 and 4 melanoma
-- Stage 4 urothelial carcinoma that has progressed on platinum therapy
-- Locally advanced or metastatic head and neck cancer
-- Refractory chronic Hodgkin’s lymphoma
-- Relapsed/refractory primary mediastinal B cell lymphoma
-- Advanced and metastatic renal cell carcinoma
-- Locally advanced or metastatic Merkel cell carcinoma
-- Hepatocellular carcinoma, in the second line after treatment with sorafenib

In other cases, a biomarker is needed to determine eligibility for immune checkpoint inhibitor therapy. The tissue marker that is most often used to determine eligibility for immune checkpoint inhibitor therapy is PD-L1 (programmed cell death ligand 1), which acts as a break on immune activation. Blocking PD-L1 with immune checkpoint inhibitors can help activate the immune system to act against a patient’s cancer. The threshold of PD-L1 expression in a tumor sample to qualify for immune checkpoint therapy depends on the type of cancer.

In addition, patients with MSI-H or MMR-deficient status solid tumors who have progressed on first-line therapy are eligible to receive pembrolizumab in the second-line setting or later.

Tumor mutation burden is also being investigated as a predictive biomarker for immune checkpoint inhibitor use.

A retrospective review of multiple phase III studies aimed to compare outcomes in patients receiving immune checkpoint inhibitors versus other standard therapies for each tumor type. Use of immune therapy was associated with more durable responses and longer length of overall survival.

However, eligibility for immune checkpoint inhibitors does not guarantee efficacy of treatment. Many more patients are eligible for immune checkpoint inhibitors than are likely to respond to them. It is probably useful to think of lack of PD-L1 expression as a negative predictive marker. In some cases in which immunotherapy use is considered, lower response rate is weighed against the possibility of durable response as well as a different and often milder side effect profile than compared with other reasonable therapies.

Full Critique

The percentage of cancer patients eligible for immune checkpoint inhibitors (ICIs) has grown, but is still more than the percentage of patients who may actually benefit from them.

"Our study is the first to quantify the estimated eligibility and response of immunotherapy checkpoint inhibitor drugs in order to get a more informed sense of their potential use and benefit," noted the study's lead author, Alyson Haslam, PhD, of the Knight Cancer Institute of Oregon Health & Science University in Portland. "This is important to understand because there are sometimes inflated expectations of what these drugs can do, and more objective estimates can help us to be more realistic about their benefit, as we engage in clinical conversations and in conversations about policy and regulations."

The study, published in JAMA Network Open, was a retrospective cross-sectional analysis providing annual estimations of the percentage of U.S. patients with cancer who are eligible for ICIs and may benefit. Haslam and her colleague Vinay Prasad, MD, MPH, also of Knight, used annual cancer deaths from American Cancer Society statistics as an estimate of the annual incidence of advanced metastatic disease. These were considered the pool of potential candidates and were adjusted per the U.S. Food and Drug Administration labels and qualifiers by tumor type -- for example, programmed death-ligand 1 (PD-L1)–positive tumors only -- to determine the percentage of patients eligible to receive ICIs.

Six ICIs were approved for 14 indications from March 25, 2011 through August 17, 2018. The estimated percentage of patients with cancer who were eligible for checkpoint inhibitor drugs increased from 1.54% in 2011 to 43.63% in 2018. The percentage of patients with cancer estimated to respond to checkpoint inhibitor drugs was 0.14% in 2011 when ipilimumab was approved for unresectable or metastatic melanoma and increased to 12.46% by 2018, the research showed.

"Patients whose tumors exhibit a high PD-L1 status respond better than patients whose tumors exhibit a low PD-L1 status, and yet the eligibility and response estimates were higher for patients with tumors that exhibit a low PD-L1 status," Haslam told the Reading Room. "The reason is that more NSCLC patients have tumors that have a low expression of PD-L1 (25%) than a high expression (75%). It was also striking that for some of the cancers with the highest number of people dying from them, such as prostate and pancreatic cancers, there were no checkpoint inhibitor drugs approved for them."

The researchers used the most favorable data -- i.e., the highest response rate of all drugs for that indication -- regardless of which drugs were actually prescribed. "This would likely lead to an overestimation of benefit," Haslam continued. "In reality, the benefit would be much less, since response rates in trials are typically higher than in clinical practice, and not all patients are prescribed or take these drugs, due to patient preferences, costs, and access. Moreover, we did not include the potential harms from these drugs, which would reduce the benefits, in our estimates."

She said there may be several explanations for why there are increasing differences in the estimated eligibility and response for FDA-approved checkpoint inhibitors: "One reason may be that the later-approved drugs were being approved for situations when cancers have failed to respond to other treatment options or that there are few good options and checkpoint inhibitors may be an alternative, albeit one that induces a low response. Also, the economic potential of ICIs is high and drug manufacturers are trying to capture a bigger market share by defining more purposes for their drugs. There is little incentive for these companies to show that these drugs lead to a clinically meaningful response as long as they can show statistical significance or for the companies to define biomarkers that limit market share."

Haslam said that randomized clinical trials need to be performed to assess the efficacy and response of the drugs in an earlier setting, but while this would increase the eligibility, it may not necessarily increase the benefit because patients may respond similarly to already approved drugs.

Rational Biomarker Evaluation

Rational biomarker evaluation is important to improve the ICI therapeutic window, she emphasized: "Our charts show an increasing difference between patients who are eligible for and those who benefit from these drugs, suggesting a need for better identification of who actually benefits. For example, much of the total response to checkpoint inhibitors is seen in patients with NSCLC, but trials have shown that these drugs produce a different response, depending on PD-L1 status of the patient's tumor. Patients whose tumors express a high percentage of PD-L1 have a higher response rate than those with a low expression of this protein."

New cancer drugs may be game changers for some patients, but "the reality is that for most patients, this is not the case," Haslam said. "As such, we need to have more objective expectations of the overall response these drugs can produce and not allow the hype to cause us to forget about the realities and risks."

Findings are 'Sobering'

In an accompanying editorial, Daniel V.T. Catenacci, MD, of the University of Chicago, and co-authors called the reported benefit ratios "underwhelming," and said the "current gap between eligibility and benefit is larger than that found in the similar assessment of genomic-based therapy -- 8.33% vs 4.9%, respectively."

The observations in the article "are sobering and remind us to keep expectations of ICIs realistic," the editorialists continued. "As the dust settles and the wave of hysteria ebbs, studies like this lend support to physicians as they attempt to explain to most of their patients with cancer the reason they are not receiving ICIs -- because these drugs are not appropriate for them."

ICIs do lead to durable responses. For example, a comparative analysis of 19 studies involving 11,640 patients treated in 42 treatment arms showed that the mean proportion of patients who had a durable response was 2.3 times higher in those treated with an ICI (25%) compared with those treated in the control arms (11%). Durable responses were more frequent in patients treated with anti–PD-1/PD-L1 agents (28%) than in patients treated with anti–CTLA-4 agents (18%).

The researchers, led by Elvire Pons-Tostivint, MD, of the Institut Paris, concluded that "durable responses were more frequent in patients treated with ICIs, although they also occurred in patients treated with other drug classes."

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